Our long-term goal is to advance cure rates for children with malignant solid tumors. The restructured program has an increased focus on developmental therapeutics, testing laboratory driven hypotheses developed from non-mammalian and mammalian experimental systems, in unique xenograft models of childhood cancers, with subsequent design of clinical trials that simulate schedules and systemic exposures found optimal in these models. This approach has been validated through our clinical project, where camptothecins, drugs that target DNA topoisomerase I, have demonstrated very significant activity in Phase I/II trials in pediatric patients. In this application we propose studies that will lead to a greater understanding of sensitivity or resistance to topoisomerase inhibitors, and will start of integrate cytotoxic agents with inhibitors of signal transduction pathways. Project 23 continues studies of mTOR signaling in growth, and survival of tumor cells. Studies will explore the therapeutic strategy of combining the mTOR inhibitor CCI-779, a rapamycin ester, in combination with IGF-I receptor antagonists and cytotoxic agents. Project 24 builds on the finding that hypomorphic alleles of genes that regulate cell cycle checkpoints in yeast confer dramatic hypersensitivity to camptothecin and rapamycin. Human homologues will be cloned, their function defined and their role in determining drug sensitivity in mammalian cells determined. Project 25 will focus on how know DNA damage response pathways determine cellular fate to camptothecins, and how hypoxia induced stress influences p53-directed cell fate. Project 26 will focus on how hypoxia or nutritional stress influences cellular sensitivity to topoisomerase II-targeted drugs and DNA cross-linking drugs through the unfolded protein response pathway. Project 27 builds on results showing that ZD1839 (an ErbB1 inhibitor) potently inhibits ABC transporters (BCRP/MRP4) that confer resistance to camptothecin drugs. The role of ZD1839 in reversing drug resistance, and altering the pharmacology of clinically used camptothecins will be explored. Project 10 comprises Phase I and II clinical trials with topotecan and irinotecan each of which is based on our laboratory and preclinical data. These protocols are supported by pharmacokinetic, and pharmacogenomic studies that ensure optimal systemic exposure, and biological studies designed to increase our understanding of parameters that determine therapeutic efficacy of camptothecin-based topoisomerase I inhibitors used alone or in combination. We will also evaluate the rapamycin ester, CCI-779, alone or in combination with vincristine, to test whether mTOR-targeted therapy will have therapeutic significance in children with solid malignancies.
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